WO2002090317A1 - Substituierte cyclohexan-1,4-diaminderivate - Google Patents

Substituierte cyclohexan-1,4-diaminderivate Download PDF

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Publication number
WO2002090317A1
WO2002090317A1 PCT/EP2002/005051 EP0205051W WO02090317A1 WO 2002090317 A1 WO2002090317 A1 WO 2002090317A1 EP 0205051 W EP0205051 W EP 0205051W WO 02090317 A1 WO02090317 A1 WO 02090317A1
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WIPO (PCT)
Prior art keywords
unsubstituted
polysubstituted
mono
saturated
unbranched
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PCT/EP2002/005051
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German (de)
English (en)
French (fr)
Inventor
Bernd Sundermann
Hagen-Heinrich Hennies
Werner Englberger
Babette-Yvonne Kögel
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Grünenthal GmbH
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Priority to BR0209580-7A priority Critical patent/BR0209580A/pt
Priority to EP02738038A priority patent/EP1392641B1/de
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to SK1379-2003A priority patent/SK287319B6/sk
Priority to AU2002312883A priority patent/AU2002312883B2/en
Priority to JP2002587399A priority patent/JP2004533439A/ja
Priority to CN028137531A priority patent/CN1533374B/zh
Priority to NZ529147A priority patent/NZ529147A/en
Priority to MXPA03010134A priority patent/MXPA03010134A/es
Priority to KR1020037014568A priority patent/KR100895778B1/ko
Priority to DE50209929T priority patent/DE50209929D1/de
Priority to DK02738038T priority patent/DK1392641T3/da
Priority to IL15878202A priority patent/IL158782A0/xx
Priority to SI200230571T priority patent/SI1392641T1/sl
Priority to CA2446461A priority patent/CA2446461C/en
Priority to HU0400888A priority patent/HU228253B1/hu
Publication of WO2002090317A1 publication Critical patent/WO2002090317A1/de
Priority to NO20034930A priority patent/NO328600B1/no
Priority to IL158782A priority patent/IL158782A/en
Priority to US10/704,329 priority patent/US7276518B2/en
Priority to ZA2003/09522A priority patent/ZA200309522B/en
Priority to HK05102616.5A priority patent/HK1070049A1/xx
Priority to CY20071100630T priority patent/CY1106468T1/el

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    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/36—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing at least two amino groups bound to the carbon skeleton
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Definitions

  • the present invention relates to substituted cyclohexane-1, 4-diaminde vate, processes for their preparation, medicaments containing these compounds and the use of substituted cyclohexane-1, 4-diamine derivatives for the production of medicaments.
  • the heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, pp. 532-535), which belongs to the family of opioid receptors and in many regions of the brain and the spinal cord can be found (Mollereau et al., FEBS Letters, 341, 1994, pp. 33-38, Darland et al., Trends in Neurosciences, 21, 1998, pp. 215-221).
  • the peptide is characterized by high affinity, with a K ⁇ value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, pp.
  • the ORL1 receptor is homologous to the ⁇ , K and ⁇ opioid receptors and the amino acid sequence of the nociceptin peptide is very similar to that of the known opioid peptides.
  • the activation of the receptor induced by the nociceptin leads to an inhibition of the adenylate cyclase via the coupling with G j / 0 proteins (Meunier et al., Nature 377, 1995, pp. 532-535).
  • G j / 0 proteins Meunier et al., Nature 377, 1995, pp. 532-535.
  • there are functional similarities of the ⁇ , K and ⁇ opioid receptors with the ORL1 receptor with regard to the activation of the potassium channel (Matthes et al., Mol. Pharmacol.
  • nociceptin peptide shows pronociceptive and hyperalgesic activity in various animal models (Reinborg et al., Science 270, 1995, pp. 792-794; Hara et al,. Br. J. Pharmacol. 121, 1997, pp. 401-408). These findings can be explained as an inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, S131-134; and Neuroscience 75, 1996, pp. 333-337). An anxiolytic activity of nociceptin could also be demonstrated in this connection (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
  • Nociceptin inhibits the activity of kainate or glutamate stimulated dorsal root ganglion neurons (Shu et al., Neuropeptides, 32, 1998, 567-571) or glutamate stimulated spinal cord neurons (Faber et al., Br. J. Pharmacol., 119, 1996, p 189-190); it has an antinocieeptic effect in the tail flick test in the mouse (King et al., Neurosci.
  • the ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes. These include learning and memory formation (Sandin et al., Eur. J. Neurosci., 9, 1997, pp. 194-197; Manabe et al., Nature, 394, 1997, pp. 577-581), hearing ( Nishi et al., EMBO J., 16, 1997, pp. 1858-1864), food intake (Pomonis et al., NeuroReport, 8, 1996, pp. 369-371), regulation of blood pressure (Gumusel et al., Life Sci., 60, 1997, pp. 141-145; Campion and Kadowitz, Biochem. Biophys. Res.
  • analgesia stimulation and regulation of food intake, influence on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of morphine, anxiolysis, modulation of movement activity, memory disorders, epilepsy; Modulation of the neurotransmitter release, in particular of glutamate, serotonin and dopamine, and thus neurodegenerative diseases; Influencing the cardiovascular system, triggering an erection, diuresis, antinatriuresis, electrolyte balance, aterial blood pressure, water storage diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence).
  • agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is also discussed.
  • the object of the present invention was to provide pharmaceuticals which act on the nociceptin / ORL1 receptor system and thus for pharmaceuticals in particular for the treatment of the various diseases associated with this system according to the prior art or for use in the indications mentioned there are suitable.
  • the invention therefore relates to substituted cyclohexane-1,4-diamine derivatives of the general formula I, which are referred to below as connecting group (A),
  • R1 and R ⁇ are independently selected from H; C j .g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ and R ⁇ together form a ring and are CH 2 CH 2 OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3_6,
  • R ⁇ selected from H; C- ⁇ g-alkyl or C .ß-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R ⁇ is selected from C- ⁇ g-alkyl or C3_8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, C3_8-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-1.4-alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R ⁇ is selected from H, C- j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 8 selected from H, C- j ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R ⁇ together form a ring and are CH 2 CH 2 OCH2CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH 2 ) 3_6,
  • C- ⁇ g-alkyl or C3_3-cycloalkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ selected from C- ⁇ g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • C- j _7-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • R 4 when R 3 is substituted or unsubstituted phenyl and at least one of R 1 or R 2 is H or d- 8 alkyl, R 4 must not be alkyl and R 4 and R 5 must not together form a heterocycle
  • R 3 is unsubstituted phenyl and R 1 and R 2 together are (CH2) 5
  • R 4 is selected from H or C 1-6 alkyl
  • Y is not O or S and R 5 is not C- 6 -Alkyl is
  • R1 and R ⁇ are independently selected from H; C- ⁇ g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C3_8-cycloalkyl or heteroaryl bonded via C 3 alkylene, in each case mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H, or the radicals R ⁇ and R ⁇ together form a ring and CH2CH 2 OCH 2 CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • R ⁇ selected from H; C-
  • R ⁇ is selected from C ⁇ alkyl or C3_8 cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, C3_g-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C1.4-alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 or C (X) SR 9 , S (O 2 ) R 9
  • F7 selected from H, C- ⁇ g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • radicals R 7 and R ⁇ together form a ring and CH 2 CH2 ⁇ CH 2 CH2, CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • R10 selected from H; C ⁇ alkyl or C3_8-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ selected from Ci.g-alkyl or C3_8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R ⁇ is selected from C3_3-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 11 H selected with R 11 H, C-
  • R ⁇ and R 2 are independently selected from H; C j .g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C3_8-cycloalkyl or heteroaryl bonded via C 1-4 alkylene, in each case mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R is selected from C ⁇
  • R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 or C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C ⁇ alkyl or C3_8 cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 8 selected from H, C-
  • R 10 selected from H; C-
  • R ⁇ selected from C ⁇ .g-alkyl or C3_g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 5 is selected from C3_g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , -
  • R1 and R 2 are independently selected from H; C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R ⁇ and R 2 together form a ring and mean CH2CH 2 OCH 2 CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3_6,
  • R ⁇ selected from H; C 1-6 alkyl or C3_8 cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R3 is selected, in each case saturated from C j .g-alkyl or C3_g-cycloalkyl or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Heteroaryl, unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-
  • R 4 is selected from H, C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, Ci.g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • _4-alkyl group bound Aryl, C3_g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 8 selected from H, C ⁇
  • R ⁇ O selected from H; C 1 -C 6 -alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl bonded via C 3 alkylene, 03.3 cycloalkyl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;
  • R ⁇ selected from C- ⁇ g-alkyl or C3_8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R is selected from C3_g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • radicals R and R 2 together form a ring and denote CH 2 CH2 ⁇ CH 2 CH2, CH 2 CH 2 NR 6 CH 2 CH 2 or (CH 2) 3_6 mean
  • R ⁇ selected from H; C- ⁇ g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or C j _3-alkylene-bound aryl, C3_g-cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted;
  • R 8 is selected, in each case saturated from C j .g alkyl or C 3-8 cycloalkyl, or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C j _4- alkyl group bound aryl, C3_g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 7 selected from H, C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 8 selected from H, C ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R 8 together form a ring and denote CH 2 CH2 ⁇ CH 2 CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH2). 3 6 mean
  • R10 selected from H; C 1-6 -alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ selected from C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • Aryl, C3_g-cycloalkyl or heteroaryl in each case unsubstituted or mono- or polysubstituted;
  • R5 is selected from C3_8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • C 1-2 alkyl is C1- or C2-alkyl, C ⁇ -3 alkyl for C1-, C2- or C3-alkyl, C ⁇ -4 -alkyl for C1-, C2-, C3- or C4-alkyl C 1-5 alkyl for C1, C2, C3, C4 or C5 alkyl, C 1-6 alkyl for C1, C2, C3, C4, C5 or C6 alkyl, C 1-7 alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C 1-8 -alkyl for C1-, C2-, C3-, C4-, C5- , C6, C7 or C8 alkyl, C 1-10 alkyl for C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and C ⁇ - ⁇ 8 -alkyl for C1-, C2-, C3-, C4-, C5-, C
  • C 3-4 -cycloalkyl stands for C3- or C4-cycloalkyl, C 3- -cycloalkyl for C3-, C4- or C5-cycloalkyl, C 3-6 -cycloalkyl for C3-, C4-, C5- or C6- Cycloalkyl, C 3-7 -cycloalkyl for C3-, C4-, C5-, C6- or C7- Cycloalkyl, C 3-8 cycloalkyl for C3, C4, C5, C6, C7 or C8 cycloalkyl, C 4-5 cycloalkyl for C4 or C5 cycloalkyl, C 4-6 cycloalkyl for C4 -, C5- or C6-cycloalkyl, C 4-7 -cycloalkyl for C4-, C5-, C6- or C7-cycloalkyl, C 5-6 -cycloalkyl for C5- or C6-cycloalky
  • cycloalkyl also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O.
  • cycloalkyl also includes, in particular, one or more, preferably mono-, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system.
  • the alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl , Pentyl, 1, 1-Dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, Hexyl, 1-Methylpentyl, Cyclopropyl, 2-Methylcyclopropyl, Cyclopropylmethyl, Cyclobutyl, Cyclopentyl, Cyclopentylmethyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, but also Adamantyl , CHF2, CF3 or CH2OH and pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane.
  • Particularly preferred substituents here are F, Cl and OH.
  • the hydrogen radical can also be substituted by OC ⁇ -3 alkyl or C- ⁇ - 3 alkyl (in each case one or more times substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3-6 is -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH2-CH2- and CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, (CH 2 ) 1-4 is -CH 2 - , - CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -, (CH 2 ) 4-5 means - CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - to understand, etc.
  • An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.
  • a heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be mono- or polysubstituted.
  • heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1,2,5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane and benzodioxane , Carbazole, indole and quinazoline.
  • the radical R 22 stands for H, a C ⁇
  • the radicals R 28 and R 24 identical or different, for H, a C ⁇ - j Q-alkyl, preferably a C-
  • salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
  • This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salts in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation ,
  • physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are compatible.
  • this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2 -dihydro1b6- benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, a -Liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
  • the hydrochloride salt is particularly preferred.
  • the term salt formed with a physiologically compatible acid is taken to mean salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • the hydrochloride is particularly preferred.
  • physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1, 2-dihydro1 ⁇ 6 - benzo [ d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid
  • physiologically compatible salt with cations or bases means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and / or mammal - are compatible.
  • the salts of the alkali and alkaline earth metals are also particularly preferred, however, with NH + , but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
  • the term salt formed with a physiologically compatible cation is understood to mean salts of at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically compatible, in particular when used in humans and / or mammals.
  • the salts of the alkali and alkaline earth metals but also NH + are particularly preferred, but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 'and R 2 are independently selected from H; C- j .g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R ⁇ and R 2 together form a ring and are CH 2 CH 2 OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3 .g,
  • R6 selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R1 and R 2 are independently selected from H; C ⁇
  • R1 and R 2 are independently selected from methyl or ethyl or the radicals R ⁇ and R 2 together form a ring and are ( ⁇ 2) 5.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 1 and R 2 together form a ring and are CH2CH2OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3_g,
  • R ⁇ selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R ⁇ and R 2 together form a ring and mean ( ⁇ 2) 4.5,
  • R1 and R 2 together form a ring and mean ( ⁇ 2) 5.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R ⁇ and R 2 are independently selected from H; C- ⁇ g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R1 and R 2 are independently selected from methyl or ethyl.
  • the substituted cyclohexane-1, 4-diamine derivatives are structured such that according to formula I
  • R 8 is selected from Cg.g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; a saturated or unsaturated, unbranched, substituted or unsubstituted C j _2- alkyl group bound aryl, C3_g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 8 is selected from Cg.g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, each unsubstituted or mono- or polysubstituted; over a saturated, unbranched C ⁇
  • R 8 is selected from phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; phenyl, furyl or thiophenyl bonded via a saturated, unbranched C 1-4 alkyl group, in each case unsubstituted or mono- or polysubstituted.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 8 is selected from C3_g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, unbranched, substituted or unsubstituted Aryl, C3_g-cycloalkyl or heteroaryl bonded to an alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 8 is selected from C5_g-cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrimidylated or unsubstituted by pyridyl or pyrimidyl or pyrazole via a saturated, un
  • R 8 is selected from furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; over a saturated, unbranched C-
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that the formula IR 4 is H.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 4 is selected from H or C (O) R 7 ; preferably selected from R 7
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, preferably between 5 and 7 Atoms in the ring, of which, in addition to the obligatory N, 0 to 1 further heteroatoms selected from N, S or O are in the ring;
  • heterocycle formed by R 4 and R 5 may optionally be condensed with further rings,
  • aromatic and / or heteroaromatic rings preferably with aromatic and / or heteroaromatic rings, it being possible for these to be condensed with further aromatic and / or heteroaromatic rings,
  • heterocycle formed by R 4 and R 5 is condensed with one or two further rings
  • heterocycle formed by R 4 and R 5 is condensed with two further rings such that R 4 and R 5 together
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I
  • R 4 is selected from H or C j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • the substituted cyclohexane-1, 4-diaminde ⁇ ' vate are constructed such that
  • R ⁇ is selected from C3_g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R ⁇ is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, pyryl, pyrylylyl, pyrylylyl, pyrylylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyr
  • R ⁇ is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, or pyridyl, pyridyl, pyridyl, pyrrol single or multiple substituted.
  • the substituted cyclohexane-1,4-diamine derivatives are structured such that according to formula I R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , or -C (Y) -CH 2 -CH 2 -CH 2 R. 1 12
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 or -C (Y) -CH 2 -CH 2 R 12
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 ,
  • R 11 is selected from
  • _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C-
  • C- ) _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C-
  • _2-alkyl saturated, unbranched, mono- or polysubstituted or unsubstituted unsubstituted;
  • R 12 is selected from C3_g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 12 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, pyryl, pyrylylyl, pyrylylyl, pyrylylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyry
  • R 12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyridyl or pyridyl, pyridyl, pyrrol single or multiple substituted.
  • the substituted cyclohexane-1,4-diamine derivatives according to the invention are particularly preferably selected in particular from the following group:
  • the substances according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals.
  • the invention therefore furthermore relates to medicaments comprising at least one substituted cyclohexane-1,4-diamine derivative from the group of compounds according to the general formula I referred to below as (F),
  • R 1 and R 2 are independently selected from H; C 1 -C 6 -alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or C j .g alkylene bound aryl, C3_g-cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted; where R 1 and R 2 cannot both be H, or the radicals R ⁇ and R 2 together form a ring and are CH2CH 2 OCH 2 CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3_g,
  • R6 selected from H; C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or C j _3-alkylene-bound aryl, C3_g-cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted;
  • R 8 is selected from C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 4 is selected from H, C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • Aryl heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • radicals R 7 and R 8 together form a ring and are CH 2 CH 2 OCH2CH2, CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3 .g,
  • R 10 selected from H; C ⁇
  • R ⁇ selected from C-
  • R5 is selected from Cg.g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 11 H selected with R 11 H, C ⁇ _7-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C-
  • _ß-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • R 4 when R 3 is substituted or unsubstituted phenyl and at least one of R 1 or R 2 is H or C 1-8 alkyl, R 4 must not be alkyl spursiinn ddaairf and R 4 and R 5 must not together form a heterocycle,
  • the invention also further relates to medicaments comprising at least one substituted cyclohexane-1,4-diamine derivative from the group of compounds according to the general formula I referred to below as (G),
  • R1 and R 2 are independently selected from H; C-
  • radicals R- 'and R 2 together form a ring and mean CH2CH 2 OCH2CH 2> CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3_ 6 ,
  • R selected from H; C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C3_g-cycloalkyl or heteroaryl bonded via C 1-4 alkylene, in each case mono- or polysubstituted or unsubstituted; R 8 is selected from C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 4 is selected from H, C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 is selected from H, C j .g-alkyl or Cg.g cycloalkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 8 selected from H, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R 8 together form a ring and are CH2CH 2 OCH 2 CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH 2 ) 3 .g,
  • R 10 selected from H; C- ⁇ g-alkyl or C3_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl, or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, Cg.g-cycloalkyl or heteroaryl bonded via C 1-6 alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R ⁇ selected from C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R5 is selected from Cg.g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • C- _7-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O-C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • the pure stereoisomers in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically tolerable salts or salts of physiologically tolerable acids or cations; or in the form of its solvates, in particular the hydrates, and, if appropriate, containing suitable additives and / or auxiliaries and / or, if appropriate, further active ingredients.
  • the invention also relates to medicaments comprising at least one substituted cyclohexane-1,4-diamine derivative from the group of compounds according to the general formula I referred to below as (H),
  • R ⁇ and R 2 together form a ring and CH2CH2OCH2CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • R6 selected from H; C ⁇ .g-alkyl or Cg.g-cycloalkyl, each saturated or unsaturated, branched or unbranched, simple or multiply substituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, Cg.g-cycloalkyl or heteroaryl bonded via Ci.g-alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R 8 is selected from C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C ⁇
  • R 4 is selected from H, C 1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C ⁇
  • R 8 selected from H, C- j ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or the radicals R 7 and R 8 together form a ring and are CH2CH 2 OCH 2 CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH 2 ) 3 .g,
  • R ⁇ selected from H; C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, Cg.g-cycloalkyl or heteroaryl bonded via C- ⁇ g alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R ⁇ selected from C- ⁇ g-alkyl or C3_3-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 5 is selected from C3_3-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , -
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • the pure stereoisomers in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically tolerable salts or salts of physiologically tolerable acids or cations; or in the form of its solvates, in particular the hydrates, and, if appropriate, containing suitable additives and / or auxiliaries and / or, if appropriate, further active ingredients.
  • the invention also further relates to medicaments containing at least one substituted cyclohexane-1,4-diamine derivative from the group of compounds according to the general formula I referred to below as (J),
  • R ⁇ and R 2 are independently selected from H; C ⁇
  • R ⁇ and R 2 together form a ring and mean CH2CH 2 OCH 2 CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3 _g,
  • R selected from H; C- ⁇ g-alkyl or Cg.g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C3_g-cycloalkyl or heteroaryl bonded via C ⁇
  • R 8 is selected from C- ⁇ g-alkyl or Cg.g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, Cg.g-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted 0 ⁇ .4-alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 or S (O 2 ) R 9
  • R 7 selected from H, C ⁇ alkyl or C 3 _g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-
  • R 8 selected from H, C
  • radicals R 7 and R 8 together form a ring and denote CH 2 CH2 ⁇ CH 2 CH2, CH 2 CH 2 CH 2 or CH2NR 10 .g mean (CH 2) 3,
  • R10 selected from H; C ⁇ .g-alkyl or C3 _g cycloalkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ selected from C- ⁇ g-alkyl or C 3 .g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C «
  • C- j _7-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O-C- ⁇ -alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • the pure stereoisomers in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically tolerable salts or salts of physiologically tolerable acids or cations; or in the form of its solvates, in particular the hydrates, and, if appropriate, containing suitable additives and / or auxiliaries and / or, if appropriate, further active ingredients.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from one of the connecting groups (F) or (G) according to formula I, in which R1 and R 2 are independently selected from H; C ⁇ .g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R 6 selected from H; C ⁇
  • R1 and R 2 are independently selected from H; C j _4 - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R1 and R 2 are independently selected from methyl or ethyl or the radicals R 1 and R 2 together form a ring and are ( ⁇ 2) 5.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting group (H) according to formula I, in which
  • R 1 and R 2 together form a ring and are CH2CH2OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3 .g, with R 6 selected from H; C j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R 1 and R 2 together form a ring and are ( ⁇ 2) 4.5,
  • R ⁇ and R 2 together form a ring and are ( ⁇ 2) 5.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting group (J) according to formula I, in which
  • R ⁇ and R 2 are independently selected from H; C- ⁇ g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R 'and R 2 are independently selected from H; C j _4 - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R1 and R 2 are independently selected from methyl or ethyl
  • R1 and R 2 together form a ring and mean CH2CH2OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3 .g,
  • R ⁇ selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R 1 and R 2 together form a ring and are ( ⁇ 2) 4.5,
  • R ⁇ and R 2 together form a ring and are ( ⁇ 2) 5.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from one of the connecting groups (F), (H) or (J) according to formula I, in which
  • R 8 is selected from C 3 _g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, unbranched, substituted or unsubstituted C ⁇
  • R 8 is selected from C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, each unsubstituted or mono- or polysubstituted; C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, bonded via a saturated, unbranched C - ⁇ - alkyl group Pyrrolyl, pyrimidyl or pyr
  • R 8 is selected from phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; phenyl, furyl or thiophenyl bound via a saturated, unbranched C- ⁇ 2-alkyl group, in each case unsubstituted or mono- or polysubstituted.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting group (G) according to formula I, in which
  • R 8 is selected from C 3 _g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, unbranched, substituted or unsubstituted C ⁇
  • R 8 is selected from C5_g-cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl, or unsubstituted by simple means bonded via a saturated, unbranched C 1-4 alkyl group or substituted several times;
  • R 8 is selected from furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; over a saturated, unbranched C-
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G), (H) or (J) according to formula I, in which R 4 is H.
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G), (H) or (J) according to formula I, in which
  • R 4 is selected from H or C (O) R 7 ; preferably selected from R 7
  • medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G) or (H) according to formula I, in which
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, preferably with between 5 and 7 atoms in the ring, of which in addition to the obligatory N there are 0 to 1 further heteroatoms selected from N, S or O in the ring;
  • heterocycle formed by R 4 and R 5 may optionally be condensed with further rings,
  • aromatic and / or heteroaromatic rings preferably with aromatic and / or heteroaromatic rings, it being possible for these to be condensed with further aromatic and / or heteroaromatic rings,
  • heterocycle formed by R 4 and R 5 is condensed with one or two further rings
  • heterocycle formed by R 4 and R 5 is condensed with two further rings such that R 4 and R 5 together
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G) or (H) according to formula I, in which
  • R 4 is selected from H, C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • Preferred medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G), (H) or (J) according to formula I, in which
  • R is selected from C 3 _g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, pyryl, pyrylylyl, pyryl, pyrylylyl, pyryl, pyrylylyl, pyryl, pyridyl, pyryl, pyridyl, pyryl, pyridyl, pyryl, pyridyl, pyryl, pyridyl, pyryl, pyryl, pyridyl, pyryl, pyryl, pyri
  • R5 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, or pyridyl, pyridyl, pyrryl, pyridyl, pyridyl, pyridyl or pyridyl, pyridyl, pyridyl or pyridyl, pyridyl, pyridyl or pyridyl, pyridyl, pyridyl, pyridyl or pyridyl, pyridy
  • medicaments according to the invention contain at least one cyclohexane-1,4-diamine derivative from the connecting groups (F), (G), (H) or (J) according to formula I, in which
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 ,
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 or -C (Y) -CH 2 -CH 2 R 12
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 or -C (Y) -CH 2 R 12
  • R 11 is selected from
  • _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C ⁇
  • _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • C j _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C ⁇ _2 "Alky ' > saturated, unbranched, mono- or polysubstituted or unsubstituted unsubstituted;
  • R 12 is selected from C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 12 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl , Fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo [1, 2.5] thiazolyl or 1, 2-dihydroacenaphtenyl, pyridinyl, furanyl, Benzofuranyl, pyrazolinonyl, oxopyra
  • R 12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyridyl or pyridyl, pyridyl, pyrrol single or multiple substituted.
  • the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid dosage forms in the form of injection solutions, Drops or juices can be administered as semi-solid pharmaceutical forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of excipients etc.
  • the amounts to be used depend on whether the medicinal product is orally, orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin, mucous membranes or in the eyes to be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
  • Substituted cyclohexane-1,4-diamine derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations.
  • Formulations which can be used orally or percutaneously can release the substituted cyclohexane-1,4-diamine derivatives according to the invention in a delayed manner.
  • other active substances known to the person skilled in the art can be added to the medicaments according to the invention.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 0.005 to 1000 mg / kg, preferably 0.05 to 5 mg / kg, of at least one substituted cyclohexane-1,4-diamine derivative according to the invention are applied.
  • the medicament contains, in addition to at least one substituted cyclohexane-1,4-diamine derivative, an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane ,
  • a substituted cyclohexane-1,4-diamine derivative according to the invention is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
  • substituted cyclohexane-1, 4-diamine derivatives according to the invention can be used for the production of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
  • the invention therefore furthermore relates to the use of substituted cyclohexane-1,4-diamine derivatives according to the general formula I, hereinafter referred to as the connecting group (K),
  • R1 and R 2 are independently selected from H; C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇ . 3- alkylene-bonded aryl, C 3 _g-cycloalkyl or heteroaryl, each mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R ⁇ and R 2 together form a ring and mean CH 2 .g CH2 ⁇ CH 2 CH2, CH 2 CH 2 CH 2 or CH2NR 6 (CH 2) 3,
  • R6 selected from H; C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R 8 is selected from C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; over a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Aryl, C 3 _g-cycloalkyl or heteroaryl which are bonded to an alkyl group, in each case unsubstituted or singly or multiply substituted;
  • R 4 is selected from H, C ⁇
  • R 7 selected from H, C- j .g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, C 3 _g-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 8 selected from H, C ⁇
  • radicals R 7 and R 8 together form a ring and denote CH 2 CH2 ⁇ CH 2 CH2, CH 2 CH 2 CH 2 or CH2NR 10 .g mean (CH 2) 3,
  • R 10 selected from H; C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R5 is selected from C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • R 3 when R 3 is substituted or unsubstituted phenyl and at least one of R 1 or R 2 is H or C 1-8 alkyl, R 4 must not be alkyl and R 4 and R 5 must not together form a heterocycle
  • the invention therefore furthermore relates to the use of substituted cyclohexane-1,4-diamine derivatives according to the general formula I, hereinafter referred to as the connecting group (L),
  • R1 and R 2 are independently selected from H; C j .g alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C 3 .g-cycloalkyl or heteroaryl bonded via C ⁇ 3 -alkylene, in each case mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R6 selected from H; C ⁇ g-alkyl or C 3 _g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-. 3- alkylene-bonded aryl, C 3 .g-cycloalkyl or heteroaryl, each mono- or polysubstituted or unsubstituted;
  • R 8 is selected from C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-
  • R 4 is selected from H, C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C-
  • R 8 selected from H, C ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R 8 together form a ring and CH2CH 2 OCH 2 CH2, CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • _g-alkyl or C 3 .g-cycloalkyl each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or C- j _ 3 alkylene bound aryl, C 3 .g- cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted;
  • R ⁇ selected from C-
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • the invention therefore furthermore relates to the use of substituted cyclohexane-1,4-diamine derivatives according to the general formula I, hereinafter referred to as the connecting group (M),
  • R 1 and R 2 together form a ring and are CH2CH2OCH2CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3 .g,
  • R selected from H; C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C «
  • R 8 is selected from C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C «
  • R 7 selected from H, C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, C 3 _g-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 8 selected from H, C ⁇ _4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R 8 together form a ring and CH 2 CH2 ⁇ CH2CH 2l CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • C _g-cycloalkyl each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C ⁇
  • R ⁇ selected from C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 5 is selected from C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • _7-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) 0- C j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • the invention therefore furthermore relates to the use of substituted cyclohexane-1,4-diamine derivatives according to the general formula I, hereinafter referred to as the connecting group (N),
  • R1 and R 2 are independently selected from H; C ⁇ g-alkyl or C 3 _g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R 6 selected from H; C-
  • R 8 is selected from C 1-6 alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Aryl, C 3 .g-cycloalkyl or heteroaryl bonded to an alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 or
  • R 7 selected from H, C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; aryl, C 3 _g-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 alkyl group, in each case unsubstituted or mono- or polysubstituted;
  • R 8 selected from H, C ⁇ alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or
  • radicals R 7 and R 8 together form a ring and are CH2CH 2 OCH 2 CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH 2 ) 3 .g,
  • R10 selected from H; C 1-6 alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R ⁇ selected from C-
  • R5 is selected from C 3 _g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • H C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically tolerable salts or salts of physiologically tolerable acids or cations; or in the form of their solvates, in particular the hydrates; for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
  • the ORL1 receptor plays a role in addition to its function in the pain process, in a large number of other physiological processes, in particular of medically relevant importance, so that a further subject of the invention is the use of substituted compounds (O) referred to below Cyclohexane-1, 4-diamine derivatives according to the general formula I,
  • R ⁇ and R 2 are independently selected from H; C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or C ⁇ _ 3 -alkylene-bound aryl, C 3 .g-cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted; where R 1 and R 2 cannot both be H, or R ⁇ and R 2 together form a ring and mean CH 2 .g CH2 ⁇ CH 2 CH2, CH 2 CH 2 CH 2 or CH2NR 6 (CH 2) 3,
  • R6 selected from H; C ⁇ _g-alkyl or C 3 .g-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R 8 is selected from C ⁇ .g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-
  • R 4 is selected from H, C ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 , S (O 2 ) R 9
  • R 7 selected from H, C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, heteroaryl, each unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-
  • radicals R 7 and R 8 together form a ring and are CH 2 CH 2 OCH2CH2, CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3 .g,
  • R 1 ⁇ selected from H; C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C 3 .g-cycloalkyl or heteroaryl bonded via C ⁇ 3 -alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R ⁇ selected from C-
  • R5 is selected from C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , - CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , - C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 11 H selected with R 11 H, C- j _7-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C- j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with further rings,
  • a substituted cyclohexane-1,4-diamine derivative used is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
  • R1 and R 2 are independently selected from H; C- ⁇ g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R ⁇ and R 2 together form a ring and mean CH 2 .g CH2 ⁇ CH 2 CH2, CH 2 CH 2 CH 2 or CH2NR 6 (CH 2) 3,
  • R6 selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R- 'and R 2 are independently selected from H; saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H,
  • R1 and R 2 are independently selected from methyl or ethyl or the radicals R ⁇ and R 2 together form a ring and are (CH2) s.
  • R ⁇ and R 2 together form a ring and CH2CH2OCH2CH2, CH 2 CH2NR 6 CH 2 CH2 or (CH 2 ) 3 . 6 mean
  • R selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R ⁇ and R 2 together form a ring and denote (0 ⁇ ) 4.5
  • R ⁇ and R 2 together form a ring and denote (0 ⁇ ) 5.
  • R 'and R 2 are independently selected from H; C ⁇ g - alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R 1 and R 2 cannot both be H, preferably
  • R1 and R 2 are independently selected from H; C-
  • R1 and R 2 are independently selected from methyl or ethyl
  • R- 'and R 2 together form a ring and are CH2CH2OCH2CH2, CH2CH 2 NR 6 CH 2 CH2 or (CH 2 ) 3 .g,
  • R selected from H; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R ⁇ and R 2 together form a ring and mean ( ⁇ 2) 4.5,
  • R ⁇ and R 2 together form a ring and are ( ⁇ 2) 5.
  • R 8 is selected from C 3 .g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, unbranched, substituted or unsubstituted C-
  • R 8 is selected from C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, each unsubstituted or mono- or polysubstituted; C5_g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or simply pyrazinyl, bonded via a saturated, unbranched C ⁇ 2-alky
  • R 8 is selected from phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; phenyl, furyl or thiophenyl bound via a saturated, unbranched C- ⁇ 2-alkyl group, in each case unsubstituted or mono- or polysubstituted.
  • R 8 is selected from C 3 .g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; via a saturated or unsaturated, unbranched, substituted or unsubstituted C
  • R 8 is selected from C5_g-cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; over a saturated, unbranched C ⁇
  • R 8 is selected from furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, each unsubstituted or mono- or polysubstituted; via a saturated, unbranched C j _2 alkyl group bonded phenyl, furyl or thiophenyl, respectively unsubstituted or singly or multiply substituted.
  • R 4 is selected from H or C (O) R 7 ; preferably selected from R 7
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, preferably with between 5 and 7 atoms in the ring, of which in addition to the obligatory N there are 0 to 1 further heteroatoms selected from N, S or O in the ring;
  • heterocycle formed by R 4 and R 5 may optionally be condensed with further rings, preferably with aromatic and / or heteroaromatic rings, it being possible for these to be condensed with further aromatic and / or heteroaromatic rings,
  • heterocycle formed by R 4 and R 5 is condensed with one or two further rings
  • heterocycle formed by R 4 and R 5 is condensed with two further rings such that R 4 and R 5 together
  • R 4 is selected from H, C ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted,
  • R5 is selected from C _g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R5 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, pyryl, pyrylylyl, pyrylidyl, pyrylylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyry
  • R is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, unsubstituted or pyrubyl, pyrrole or substituted several times.
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C ( Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or -C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 or -C (Y) -CH 2 -CH 2 R 12
  • R 5 is selected from -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 or -C (Y) -CH 2 R 12
  • R 11 is selected from
  • _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C j _4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • _4-alkyl saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C (O) O- C-
  • R 12 is selected from C 3 _g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
  • R 12 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, pyryl, pyrylylyl, pyrylylyl, pyrylylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyrylyl, pyry
  • R 12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyridyl or pyridyl, pyridyl, pyrrol single or multiple substituted.
  • Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, which requires treatment of pain, in particular chronic pain, by administration of a therapeutically viable dose of a substituted cyclohexane 1 according to the invention , 4-diamine derivative, or a medicament according to the invention.
  • Another object of the invention is a process for the preparation of the substituted cyclohexane-1, 4-diamine derivatives according to the invention as set out in the following description and examples.
  • a cyclohexane-1,4-dione of the formula II protected with the groups S 1 and S 2 is converted into a protected N-substituted 1-amino-4- in the presence of a compound of the formula HNR 01 R 02 with a cyanide, preferably potassium cyanide.
  • a cyanide preferably potassium cyanide.
  • the protective groups S 1 and S 2 are split off, so that a 4-substituted 4-aminocyclohexanone derivative according to formula IV is formed;
  • R 1 , R 2 , R 3 R 4 and R 5 have the meaning given for connecting group (A) according to formula I.
  • R 01 and R 02 are independently selected from H; H-protected; C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R 01 and R ⁇ together form a ring and are CH2CH 2 OCH 2 CH2, CH 2 CH2NR 06 CH 2 CH2 or (CH 2 ) 3 .g, with R 06 selected from H; H-protected; C j .g alkyl or C 3 _g cycloalkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via C-
  • R 04 is selected from H, H-protected; C j .g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 05 is selected from H, H with a protecting group; C 3 .g- cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; -CHR 11 R 12 , -CHR 11 - CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , - CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 or - C (Y) -CH 2 -CH 2 -CH 2 R 12
  • R 04 and R 05 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, and S 1 and S 2 are independently selected from protective groups or together represent a protective group, preferably monoacetal.
  • Alkylation is also understood to mean reductive amination, since it leads to the same result.
  • Another preferred subject matter of the invention is a process for producing a substituted cyclohexane-1, 4-diamine derivative according to the invention, which is referred to below as the alternative process, and has the following steps:
  • the cyclohexanonitrile derivative of the formula VII is reacted with organometallic reagents, preferably Grignard or organolithium reagents, of the formula metal R 3 and finally the protective groups S 1 and S 2 are split off, so that a cyclohexane-1,4-diamine derivative according to formula V is formed,
  • organometallic reagents preferably Grignard or organolithium reagents
  • R 1 , R 2 , R 3 R 4 and R 5 have the meaning given for connecting group (A) according to formula I.
  • R 01 and R 02 are independently selected from H; H-protected; C- ⁇ g-alkyl or C 3 _g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C 3 _g-cycloalkyl or heteroaryl bonded via C- ⁇ 3 alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R 06 selected from H; H-protected; C- ⁇ g-alkyl or C 3 .g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C 3 _g-cycloalkyl or heteroaryl bonded via C- ⁇ 3 alkylene, in each case mono- or polysubstituted or unsubstituted;
  • R 04 is selected from H, H-protected; C- ⁇ g-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R 04 and R 05 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted,
  • S 1 and S 2 are independently selected from protective groups or together represent a protective group, preferably monoacetal.
  • the protective groups on H in R 01 , R 02 , R 04 , R 05 and / or R 06 are selected from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.
  • step d takes place in the presence of ammonium formate, ammonium acetate or NaCNBH 3 .
  • ether means diethyl ether, "EE” ethyl acetate and “DCM” dichloromethane.
  • equivalents means substance equivalent
  • mp means melting point or melting range
  • RT means room temperature
  • vol.% Volume percent
  • aqueous phase was extracted twice with 250 ml of ether each time, the extracts combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 60.0 g of dimethyl- (8-phenyl-1,4-dioxa-spiro [4.5] dec-8-yl) amine were obtained.
  • aqueous phase was washed twice with 250 ml of ether extracted, the extracts combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 78.4 g of crude product were obtained, which mainly consisted of (8-benzyl-1,4-dioxa-spiro [4.5] dec-8-yl) dimethyl-amine and was reacted further without additional purification.
  • Example 4 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1, 4-diamine hydrochloride, more polar diastereomer
  • 820 mg of the more polar diastereomer of 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1, 4-diamine were also obtained, which were dissolved in 6.6 ml of 2-butanone and addition of 25 , 2 ul water followed by 354 ul chlorotrimethylsilane and stirring overnight in 793 mg of the corresponding hydrochloride.
  • Example 13 1-Benzyl- ⁇ / '- (1 / - / - indol-3-ylmethyl) - ⁇ /, ⁇ / -dimethylcyclohexan-1, 4-diamine dihydrochloride
  • the oxime obtained was suction filtered, washed with water (3 ⁇ 25 ml) and dried in a desiccator. 15.6 g of 1 / - / - indole-3-carbaldehyde (Z) oxime with a melting point of 190-193 ° C. were obtained.
  • Example 14 1-Benzyl- ⁇ / '- [2- (1 - / - indol-3-yl) -1-methylethyl] - ⁇ /, ⁇ / -dimethylcyclohexane-1,4-diamine, cis / trans mixture
  • Example 16 1-Benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexan-1, 4-diamine dihydrochloride, cis / trans mixture 266 mg of 1-aminoindane and 462 mg of 4-benzyl-4-dimethylamino-cyclohexanone (see Example 3) were dissolved in dry 1,2-dichloroethane under argon and stirred with 2 g of sodium sulfate at RT for 24 hours. 600 mg of sodium triacetoxyborohydride were added to this mixture and the mixture was stirred at RT for two hours. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4 x 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel using ethyl acetate. 696 mg of 1-benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexan-1, 4-diamine were obtained as a colorless oil. To prepare the hydrochloride, the base was dissolved in 2-butanone (10 ml) and mixed with 1.85 M ethanolic hydrochloric acid (2.80 ml). The precipitated solid was suction filtered and dried.
  • Example 18 / V- (1 - / - Indol-5-yl) - ⁇ /, ⁇ / -dimethyl-1-phenylcyclohexane-1, 4-diamine 264 mg of 5-aminoindane and 434 mg of 4-dimethylamino-4-phenyI-cyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred at RT for 24 hours. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4 x 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. Chromatograph the crude product with ethyl acetate / ethanol (1: 1) on silica gel. 315 mg of ⁇ / , - (1H-indol-5-yl) - ⁇ /, ⁇ / -dimethyl-1-phenylcyclohexane-1, 4-diamine were obtained as a white solid (mp. 191-192 ° C).
  • Example 19 N '- (1 H-Indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine, cis / trans mixture
  • Example 20 N '- (1 H-Indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine, less polar diastereomer
  • the mother liquor obtained in Example 19 was concentrated. 173 mg of the nonpolar diastereomer of N '- (H-indol-3-ylmethyl) -N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine were obtained (mp. 170-178 ° C).
  • Tryptamine (320 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After adding 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (229 ⁇ l) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 3 days at RT. For working up, the reaction mixture was mixed with water (20 ml). The organic phase was separated off, the aqueous phase extracted once with ether and then made strongly alkaline with sodium hydroxide solution. The aqueous phase was milky at pH 10. It was extracted with ethyl acetate (4 ⁇ 10 ml), the extracts combined, dried over sodium sulfate, filtered and concentrated.
  • Example 22 N '- [2- (1 H-Indol-3-yl) ethyl] -N, N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis / trans mixture
  • Example 23 N'-Indan-5-yl-N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine, non-polar diastereomer 5-Aminoindane (266 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added and the mixture was stirred at RT for 24 hours. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4 x 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product obtained is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 270 mg of the nonpolar diastereoisomer of N'-indan-5-yl-N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine were obtained as a white solid (mp. 162-164 ° C.).
  • DL- ⁇ -methyltryptamine (348 mg, 2 mmol) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. 4-Dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (229 ⁇ l) were added and the mixture was stirred at RT for one hour. Then sodium triacetoxyborohydride (550 mg) was added and the suspension was stirred at RT for four days. For working up, the reaction mixture was mixed with water (15 ml). The clear phases were separated, the aqueous phase was washed with ether (10 ml) and then made strongly alkaline with sodium hydroxide solution.
  • Example 25 N '- [2- (1 H-Indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
  • N '- [2- (1 H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine were also used obtained as a mixture of the cis / trans isomers (dark yellow oil).
  • the phases were separated, the aqueous phase was washed with ether (20 ml) and then made strongly alkaline with sodium hydroxide solution.
  • the aqueous phase was extracted with ether (2 ⁇ 10 ml) and ethyl acetate (4 ⁇ 10 ml), the combined extracts dried over sodium sulfate, filtered and concentrated.
  • the crude product obtained (686 mg) was recrystallized from a mixture of ethyl acetate / cyclohexane (35 ml / 5 ml).
  • the crude product was ethyl acetate / ethanol (1: 1) chromatographed on silica gel. 200 mg of N '- (9H-fluoren-1-yl) -N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine were obtained as a colorless oil which was used to prepare the hydrochloride in 2-butanone (5 ml) was dissolved and 1.85 M ethanolic HCl (0.7 ml) was added. The N '- (9H-fluoren-1-yl) -N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine dihydrochloride obtained was suction filtered and dried (220 mg, mp. 223-225 ° C).
  • Example 28 N'-Indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine dihydrochloride, cis / trans mixture
  • Example 29 N '- (9H-fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, cis / trans mixture
  • Example 31 1-Benzyl-N '- (1 H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexan-1, 4-diamine, cis / trans mixture
  • Example 32 N, N-dimethyl-N '- (1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
  • Example 34 N '- (2-Benzo [b] thiophene-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
  • Lithium aluminum hydride (1.16 g, 30.3 mmol) was suspended in dry diethyl ether (100 ml). Anhydrous aluminum chloride (4.04 g, 30.3 mmol) was introduced into this suspension under argon. After five minutes, a solution of benzo [b] thiophene-3-acetonitrile (5.25 g, 30.3 mmol) in dry diethyl ether (70 ml) was added. After the addition was complete, the mixture was heated to reflux for four days. Lithium aluminum hydride (930 mg) and aluminum chloride (500 mg) were again added to the reaction mixture and the mixture was heated under reflux for a further eight hours.
  • the mixture was neutralized with an aqueous solution of potassium sodium tartrate (80 ml, 20 m%). After the evolution of gas had ended, the phases were separated and the cloudy aqueous phase was suctioned off through a glass frit. The residue on the frit was washed with ethyl acetate and the clear aqueous phase extracted with ethyl acetate (3 x 50 ml). The organic phases were dried over sodium sulfate, filtered and concentrated. Crude benzo [b] thiophene-3-ylethylamine (3.7 g) was obtained as a red-brown oil.
  • Benzo [b] thiophene-3-yl-ethylamine (289 mg, 1, 6 mmol) was dissolved under argon in dry 1, 2-dichloroethane (10 ml) and after the addition of 4-dimethylamino-4-phenylcyclohexanone (354 mg, 1, 6 mmol) and sodium sulfate (2 g) stirred at RT for one hour.
  • Sodium triacetoxyborohydride (440 mg, 2.0 mmol) was then added in one portion to the reaction mixture. After 3 days, glacial acetic acid (4 mmol) was subsequently added and the mixture was stirred at RT for a further 24 hours.
  • Benzo [b] thiophene-3-ylethylamine (350 mg, 1.9 mmol) was dissolved under argon in dry 1, 2-dichloroethane (10 ml) and after the addition of 4-benzyl-4-dimethylaminocyclohexanone (463 mg, 2 mmol), glacial acetic acid (2 mmol) and anhydrous sodium sulfate (2 g) were stirred at RT for one hour. Sodium triacetoxyborohydride (550 mg, 2.5 mmol) was then added in one portion and the mixture was stirred at RT for four days. For working up, the mixture was diluted with 1,2-dichloroethane (10 ml) and water (15 ml).
  • the light yellow solid obtained was a mixture of ice and trans-N'- (2-benzo [b] thiophene-3-yl-ethyl) -1-benzyl-N, N-dimethyl-cyclohexan-1, 4-diamine dihydrochloride (338 mg, mp 225-229 ° C).
  • Example 36 N'-acenaphthene-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, more polar diastereomer 339 mg of acenaphthen-1-ylamine and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg of sodium triacetoxyborohydride were added to this mixture and the mixture was stirred at RT for 24 hours. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4 x 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel using ethyl acetate / ethanol (1: 1).
  • Example 36 250 mg of the nonpolar diastereomer of N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine were also obtained as a white solid, from which 1.85 M ethanolic hydrochloric acid (0.9 ml) in 2-butanone (10 ml) the corresponding dihydrochloride was precipitated (300 mg; mp 190-192 ° C).
  • DL- ⁇ -methyltryptamine (3.00 g, 17.2 mmol) was dissolved in dry 1,2-dichloroethane (10 ml) under argon.
  • 4-Dimethylamino-4-phenylcyclohexanone (3.70 g) and glacial acetic acid (1.5 ml) were added and the mixture was stirred at RT for one hour.
  • sodium triacetoxyborohydride (4.7 g) was added and the suspension for four days stirred at RT.
  • the reaction mixture was mixed with 1,2-dichloroethane (20 ml) and water (50 ml).
  • the clear phases were separated, the aqueous phase was washed with ether (2 x 20 ml) and then made strongly alkaline with five molar sodium hydroxide solution.
  • the aqueous phase was extracted with ethyl acetate (5 ⁇ 30 ml), the combined extracts dried over sodium sulfate, filtered and concentrated.
  • the crude product obtained (5.8 g of beige-brown solid) was first roughly fractionated with methanol / triethylamine (199: 1) on silica gel and then again finely cleaned.
  • Example 44 N '- (9-Ethyl-9H-carbazol-3-yl) -N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine dihydrochloride, non-polar diastereomer 421 mg of 3-amino-9-ethylcarbazole and 435 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg of sodium triacetoxyborohydride were added to this mixture and the mixture was stirred at RT for 24 hours.
  • the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated.
  • the crude product was chromatographed on silica gel using ethyl acetate / ethanol (1: 1).
  • Example 45 122 mg of the more polar diastereomer of N '- (3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine were also obtained as a white solid, from which with 1, 85 M ethanolic hydrochloric acid (0.5 ml) in 2-butanone (5 ml) the corresponding dihydrochloride was precipitated (119 mg; mp. 185-189 ° C).
  • 2-Iodothiophene (22.9 g) was dissolved in THF (80 ml) under argon and 2M isopropyl magnesium chloride (35.7 ml) in THF was added within 30 min at 0 ° C. After a reaction time of one hour at 3-5 ° C., 8-dimethylamino-1,4-dioxaspiro [4.5] decane-8-carbonitrile (10 g), dissolved in tetrahydrofuran (20 ml), was added and the mixture was stirred for 20 hours Room temperature stirred.
  • Example 49 N '- (1 H-Indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, non-polar diastereomer 970 mg of C- (1 / - / - indol-3-yl) methylamine and 1.44 mg of 4-dimethylamino-4-phenylcyclohexanone were added under argon in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (50 ml ) solved.
  • Glacial acetic acid (13.2 mmol) and 1.82 g of sodium triacetoxyborohydride were added to this mixture and the mixture was stirred at RT for 72 hours.
  • the reaction mixture was concentrated, the residue water (20 ml) and ether (30 ml) were added and the mixture was stirred vigorously.
  • the aqueous phase was separated, washed with ether (2 x 15 ml), adjusted to pH 11 with five molar sodium hydroxide solution and extracted with ethyl acetate (4 x 25 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated.
  • Example 50 N '- (1 H-Indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, more polar diastereomer
  • Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmol) was dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml). Hydroxylamine hydrochloride (3.4 g, 49.2 mmol) was added with stirring. The mixture was stirred at RT for 30 minutes and then refluxed for eight hours. A red-brown solution was created. For working up, the mixture was concentrated and the residue was freed from residual pyridine by distillation with ethanol (3 ⁇ 50 ml). The oily residue was with Water (50 ml) was added and the mixture was stirred vigorously overnight. The pink solid present was suction filtered, washed with water and dried in vacuo. 4.3 g of benzothiophene-3-carbaldehyde oxime were obtained (mp. 87-89 ° C.).
  • Benzothiophene-3-carbaldehyde oxime (3.96 g, 22.3 mmol) was dissolved in methanol (100 ml) and five molar sodium hydroxide solution (100 ml) and Devarda alloy (14.1 g) was added in portions under argon. This resulted in heating and hydrogen evolution. The mixture was stirred for 16 hours. The mixture was worked up by slowly adding water (100 ml), with a violent reaction again. The mixture was filtered through Celite, the methanol was removed in vacuo and the remaining aqueous phase was extracted with diethyl ether (3 ⁇ 50 ml).
  • the aqueous phase was adjusted to pH 8-9 with one molar sodium hydroxide solution and extracted with ether (3 ⁇ 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. The yellow, crystalline crude product (787 mg) was dissolved in methanol (7 ml) for chromatographic separation, the nonpolar diastereomer precipitating. 247 mg of the nonpolar diastereomer of N'-benzo [b] thiophene-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine were obtained as a white solid (mp. 138-140 ° C.
  • Example 51 the methanolic solution of the crude product was chromatographed on silica gel using methanol. 113 mg of the more polar diastereomer of N'-benzo [b] thiophene-3-ylmethyl-N, N-dimethyl-1-phenylcyclohexan-1, 4-diamine were obtained as a colorless oil, from which 3.3 M ethanolic hydrochloric acid (0.28 ml) in 2-butanone (10 ml) the corresponding dihydrochloride was precipitated as a white solid (120 mg; mp. 252-254 ° C).
  • the aqueous phase was adjusted to pH 8-9 with one molar sodium hydroxide solution and extracted with ether (3 ⁇ 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated. The light yellow oil obtained (904 mg) was chromatographed on silica gel with methanol. 368 mg of the nonpolar diastereomer of N'-benzo [b] thiophene-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexan-1, 4-diamine were obtained, from which with 3.3 M ethanolic hydrochloric acid ( 0.88 ml) in 2-butanone (25 ml) the corresponding dihydrochloride was precipitated (364 mg; mp. 246-255 ° C).
  • Example 54 As described for Example 54, 347 mg of the more polar diastereomer of N'-benzo [b] thiophene-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexan-1, 4-diamine were also obtained, from which with 3, 3 M ethanolic hydrochloric acid (0.83 ml) in 2-butanone (25 ml) the corresponding dihydrochloride was precipitated (418 mg; mp. 242-248 ° C).
  • a Grignard solution was prepared from magnesium (2.05 g) and 2-bromonaphthalene (17.7 g) in dry tetrahydrofuran (65 ml). This Grignard solution was stirred for a further hour at the boiling point. 8-Dimethylamino-1, 4-dioxaspiro [4.5] decane-8-carbonitrile (9.0 g) dissolved in dry tetrahydrofuran (70 ml) was then added dropwise at RT and the mixture was stirred at RT overnight. After the reaction had ended, the mixture was quenched with saturated ammonium chloride solution with ice cooling, extracted with diethyl ether (2 ⁇ 70 ml), dried over Na 2 SO 4 and concentrated.
  • the dihydrochloride of the nonpolar diastereomer of N '- [2- (1 H-indol-3-yl) ethyl] - N, N-dimethyl-1-naphthalen-2-yl-cyclohexan-1, 4-diamine was analogous to the examples described above by reductive amination of 4-dimethylamino-4-naphthalin-2-yl-cyclohexanone with tryptamine.
  • Example 57 As described for Example 57, 546 mg of the more polar diastereomer of N '- [2- (1 H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine were also used obtained (mp. 175-180 ° C), from which the corresponding dihydrochloride was obtained with chlorotrimethylsilane (573 ⁇ l) in 2-butanone / acetone (3 ml / 30 ml) (520 mg; mp. 223-229 ° C).
  • Example 42 As described for Example 42, 546 mg of the more polar diastereomer of N '- [2- (1 H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1 were also used , 4-diamine are obtained (mp. 50-55 ° C.), from which the corresponding dihydrochloride was obtained as a light pink solid with chlorotrimethylsilane (1.0 ml) in 2-butanone (50 ml) (1.1 g; mp 194 -199 ° C).
  • Example 60 As described for Example 60, (140 mg, mp. 60-65 ° C.) of the more polar diastereomer of methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) - 3- (1 H-indol-3-yl) -propionate obtained, from which the corresponding dihydrochloride was obtained as a white solid with chlorotrimethylsilane (126 ⁇ l) in 2-butanone / acetone (7 ml / 3 ml) (129 mg; mp 180-185 ° C.).
  • Example 62 N '- [2- (1 H-Indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexan-1, 4-diamine dihydrochloride, nonpolar diastereomer
  • Example 63 N'-Benzo [1, 3] dioxol-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexan-1, 4-diamine dihydrochloride, cis / trans mixture
  • the 6-fluortryptamine (410 mg) and 4-dimethylamino-4-phenylcyclohexanone (545 mg) were dissolved in THF (18 ml) and 1,2-dichloroethane (6 ml) under argon and acetic acid (138 mg) was added. After 15 minutes, sodium triacetoxyborohydride (690 mg) and THF (5 ml) were added. After 40 hours, the mixture was concentrated, the residue was taken up in 1M hydrochloric acid (20 ml) and extracted with ether (2 ⁇ 20 ml). The aqueous phase was made alkaline with 1 M sodium hydroxide solution (30 ml) and extracted with ether (3 x 30 ml).
  • G3043-foreign text-en.doc Diastereoisomer was obtained as a white solid (321 mg, mp. 185-187 ° C.), dissolved with heating in ethanol (20 ml) and mixed with 3.3N ethanolic HCl (0.79 ml). After stirring for 1 hour at RT, the white dihydrochloride of the nonpolar diamine of N '- [2- (6-fluoro-1H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenylcyclohexane-1 , 4-diamine obtained (344 mg; mp 190-195 ° C).
  • Example 65 N '- [2- (6-Fluoro-1H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, more polar diastereomer
  • Example 64 305 mg of the more polar diastereomer of N '- [2- (6-fluoro-1H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1 were also used , 4-diamine, from which the corresponding dihydrochloride was obtained in ethanol (20 ml) with 3.3N ethanolic HCl (0.73 ml) (270 mg; mp. 208-211 ° C.)
  • N- ⁇ -Methyltryptamine [2- (1 H-indol-3-yl) ethyl] methylamine, 348 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After the addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (114 ⁇ l), a voluminous precipitate formed. The suspension was stirred at RT for two hours before sodium triacetoxyborohydride (660 mg) was added. The reaction mixture was stirred at RT for two days, concentrated for working up, the residue was dissolved in water (15 ml) and diethyl ether (20 ml) and the organic phase was separated off.
  • the aqueous phase was extracted with diethyl ether (2 x 10 ml) and adjusted to pH 10 with 1 M NaOH. A white solid precipitated out, which was filtered off, washed and dried (174 mg, mp. 208-210 ° C, non-polar diastereoisomer).
  • the aqueous phase was brought to pH 11 with 1M NaOH and extracted with ethyl acetate (4 ⁇ 25 ml). The extracts were combined, dried with Na 2 SO 4 and concentrated in vacuo. The residue (469 mg) was separated by flash chromatography with methanol / triethylamine (99: 1).
  • Example 66 129 mg of the more polar diastereomer of N '- [2- (1 H-indol-3-yl) ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1, Obtain 4-diamine, which were converted into the corresponding dihydrochloride (white solid; 141 mg; mp. 198-206 ° C) in 2-butanone / acetone (15 ml / 3 ml) with chlorotrimethylsilane (121 ⁇ l) while warm.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined extracts were dried with Na 2 SO 4 , concentrated and the crude product obtained was separated on silica gel using EtOH / NH 3 (500: 1). The less polar diastereoisomer (321 mg) was obtained as a brown oil, dissolved in 2-butanone (10 ml) and converted into the dihydrochloride with chlorotrimethylsilane (270 ⁇ l) (white solid; 420 mg; mp 189-191 ° C.).
  • Example 69 N, N-Dimethyl-N '- [2- (7-methyl-1H-indol-3-yl) ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, more polar diastereomer
  • 144 mg of the more polar diastereoisomer were also obtained as a brown oil, dissolved in 2-butanone (5 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (121 ⁇ l) (white solid; 146 mg; mp 244-246 ° C).
  • Example 70 N '- [2- (5-Fluoro-1H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer
  • Example 72 N'-Acenaphthen-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, non-polar diastereomer
  • Example 74 N '- [2- (1 H-Indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophene-2-yl-cyclohexan-1, 4-diamine dihydrochloride, cis / trans mixture
  • 2-Adamantylamine (302 mg) and 4-dimethylamino-4-phenylcyclohexanone (446 mg) were dissolved in argon in a mixture of THF (15 ml) and 1,2-dichloroethane (5 ml). After 15 min the mixture was mixed with sodium triacetoxyborohydride (600 mg) and stirred for 45 hours at room temperature. For working up, the mixture was concentrated, the residue was taken up in 1M HCl (20 ml) and diethyl ether (40 ml), the phases were separated and the aqueous phase was washed with diethyl ether (2 ⁇ 30 ml).
  • the aqueous phase was made alkaline with 5M sodium hydroxide solution and extracted with diethyl ether (3 x 30 ml). After concentrating the combined organic extracts, the crude product obtained was separated by chromatography with methanol. The less polar diastereoisomer (286 mg) was dissolved in 2-butanone (15 ml) and converted into the corresponding dihydrochloride with 3.3N ethanolic hydrochloric acid (0.606 ml) (white solid; 300 mg; mp. 266 ° C.).
  • Serotonin (405 mg) was dissolved in 1,2-dichloroethane / THF (5 ml / 20 ml), with 4-dimethylamino-4-phenylcyclohexanone (500 mg), glacial acetic acid (131 ⁇ l) and annealed Sodium sulfate (2 g) was added. After stirring at RT for 1 hour, sodium triacetoxyborohydride (759 mg) was added and stirring was continued for a further two days. For working up, the mixture was concentrated, the residue was suspended in diethyl ether (15 ml), water (10 ml) and 2M HCl (1 ml), further diethyl ether (20 ml) was added and the organic phase was roughly separated.
  • the aqueous phase was first brought to pH 9 with 1M NaOH and extracted with ethyl acetate (3 ⁇ 5 ml), then adjusted to pH 11 and extracted again with ethyl acetate (5 ⁇ 10 ml).
  • the organic extracts were dried, concentrated and purified by flash chromatography (eluent: MeOH / NEt 3 99.5: 0.5). 267 mg of the nonpolar diastereoisomer (mp.
  • Example 78 As described for Example 78, 124 mg of the more polar diastereoisomer (mp. 185-187 ° C.) were also obtained and, dissolved in ethanol / 2-butanone (6 ml / 15 ml), with 3.3N ethanolic HCl (298 ⁇ l) in the corresponding dihydrochloride is transferred (white solid; 123 mg; mp. 230-233 ° C).
  • Example 80 N '- [2- (5-methoxy-1H-indol-3-yl) ethyl] -N, N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer
  • 6-methoxytryptamine (495 mg) was clearly dissolved under argon in dry 1, 2-dichloroethane and THF (5 ml / 15 ml). After adding 4-dimethylamino-4-phenylcyclohexanone (565 mg) and glacial acetic acid (148 ⁇ l), the mixture was stirred at RT for 2 h before sodium triacetoxyborohydride (858 mg) was added. The reaction mixture was stirred at RT for two days. For working up, water (15 ml) and 5.5M HCl (1.5 ml) were added to the reaction mixture.
  • the more polar diastereoisomer (320 mg; mp. 136-140 ° C.) was also obtained, dissolved in 2-butanone / acetone (15 ml / 3 ml) and converted into the corresponding dihydrochloride using chlorotrimethylsilane (310 ⁇ l) (white solid; 362 mg; mp 206-210 ° C).
  • 5-Methyltryptamine (348 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the exclusion of oxygen.
  • Glacial acetic acid (114 ⁇ l) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred at RT for 24 hours.
  • the mixture was concentrated, the residue was taken up in 1 M HCl (20 ml) and diethyl ether (40 ml), the phases were separated, the aqueous phase was extracted with diethyl ether (2 ⁇ 20 ml) and adjusted to pH 11 with 5M NaOH. The aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried with Na 2 SO 4 and concentrated. The residue was purified by chromatography with MeOH / NH 3 (500: 1).
  • Example 83 N, N-Dimethyl-N '- [2- (5-methyl-1H-indol-3-yl) ethyl] -1-phenylcyclohexane-1,4-diamine dihydrochloride, more polar diastereomer
  • 2-butanone 10 ml
  • Me 3 SiCl 224 ⁇ l, 1.76 mmol
  • Example 84 Dimethyl- [1-phenyl-4- (1, 3,4,9-tetrahydro-b-carbolin-2-yl) cyclohexyl] amine dihydrochloride
  • aqueous solution was made alkaline with 1 M NaOH (30 ml) and extracted with ether (3 x 30 ml). After drying and concentrating the combined extracts, a semi-solid crude product was obtained which, after separation by column chromatography with methanol / NH 3 (500: 3), gave the nonpolar diastereoisomer (334 mg, mp. 147-150 ° C.), which in 2-buatnone ( 20 ml) and ethanol (10 ml) dissolved under heating with 3.3M ethanolic hydrochloric acid (0.8 ml) was converted into the corresponding dihydrochloride (335 mg; mp. 264-269 ° C).
  • the mixture was concentrated, 1M HCl (20 ml) and diethyl ether (40 ml) were added, the phases were separated, the aqueous phase was extracted with diethyl ether (2 ⁇ 20 ml) and adjusted to pH 11 with 5N NaOH.
  • the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried over Na 2 S0, concentrated and the residue purified by chromatography on silica gel with methanol.
  • the less polar diastereoisomer (531 mg, 1.55 mmol) was dissolved in anhydrous pyridine (10 ml) and acetic anhydride (1.59 g, 15.59 mmol) was added with stirring. After 24 hours, the reaction mixture was mixed with a few pieces of ice and concentrated on the rotary evaporator as much as possible. 1M NaOH (20 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate (3 ⁇ 30 ml), the combined organic extracts dried with Na 2 SO 4 and concentrated.
  • 3-phenylpropylamine (676 mg) and 4-dimethylamino-4-phenylcyclohexanone (1, 086 g) were dissolved in dry 1, 2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the exclusion of oxygen.
  • Glacial acetic acid (5 mmol) and sodium triacetoxyborohydride (1.5 g, 7 mmol) were added to this mixture and the mixture was stirred at RT for 24 hours touched.
  • the mixture was concentrated and 1M HCl (20 ml) and diethyl ether (40 ml) were added to the mixture.
  • the aqueous phase was washed with diethyl ether (2 x 20 ml), separated, adjusted to pH 11 with 5N NaOH, diluted with water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried with Na 2 SO 4 and concentrated.
  • the crude product obtained was purified by chromatography on silica gel with methanol. 761 mg of the less polar diastereoisomer were obtained. 453 mg were dissolved in anhydrous pyridine (10 ml) and acetic anhydride (1.374 g) was added with stirring. After stirring at RT for 24 hours, a few pieces of ice were added and the mixture was concentrated on the rotary evaporator as far as possible.
  • rac-6-fluortryptophan methyl ester (952 mg) in 1,2-dichloroethane (approx. 30 ml) was treated under argon with 4-dimethylamino-4-phenylcyclohexanone (877 mg), sodium sulfate (2 g) and glacial acetic acid (230 ⁇ l, 4 mmol) was added. After stirring at RT for one hour, sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and stirred at RT for two days.
  • the mixture was concentrated, the mixture was adjusted to pH 11 with 5M NaOH, the phases were separated, the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml). The combined organic extracts were dried with Na 2 SO 4 and concentrated.
  • the amide obtained was purified by column chromatography with ethyl acetate / ethanol (1: 1) and (120 mg), dissolved in 2-butanone (3 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (61 ⁇ l) (white solid; 128 mg; M.p. 100-102 ° C).
  • the cyclohexane-1,4-diamine derivatives of the general formula I were investigated in a receptor binding assay with ⁇ H-nociceptin / orphanin FQ with membranes of recombinant CHO-ORL1 cells.
  • This test system was developed according to the method described by Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824) performed method presented. The concentration of ⁇ H-nociceptin / orphanin FQ was 0.5 nM in these experiments.
  • the binding assays were carried out with 20 ⁇ g membrane protein each with 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA.
  • Binding to the ORL1 receptor was determined using 1 mg each of WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubating the mixture for one hour at room temperature and then measuring in the scintillation counter Trilux (Wallac, Finland). The affinity is given as a K j value in ⁇ M.

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PCT/EP2002/005051 2001-05-09 2002-05-08 Substituierte cyclohexan-1,4-diaminderivate WO2002090317A1 (de)

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DK02738038T DK1392641T3 (da) 2001-05-09 2002-05-08 Substituerede cyclohexan-1,4-diaminderivater
DE50209929T DE50209929D1 (de) 2001-05-09 2002-05-08 Substituierte cyclohexan-1,4-diaminderivate
SK1379-2003A SK287319B6 (sk) 2001-05-09 2002-05-08 Substituované deriváty cyklohexán-1,4-diamínu, spôsob ich výroby, lieky tieto látky obsahujúce a ich použitie
AU2002312883A AU2002312883B2 (en) 2001-05-09 2002-05-08 Substituted cyclohexane-1,4-diamine derivatives
JP2002587399A JP2004533439A (ja) 2001-05-09 2002-05-08 置換されたシクロヘキサン−１，４−ジアミン誘導体
CN028137531A CN1533374B (zh) 2001-05-09 2002-05-08 取代的环己烷-1,4-二胺衍生物
EP02738038A EP1392641B1 (de) 2001-05-09 2002-05-08 Substituierte cyclohexan-1,4-diaminderivate
MXPA03010134A MXPA03010134A (es) 2001-05-09 2002-05-08 Derivados de ciclohexan-1-4-diamina sustituidos.
IL15878202A IL158782A0 (en) 2001-05-09 2002-05-08 Substituted cyclohexane-1,4-diamine derivatives
BR0209580-7A BR0209580A (pt) 2001-05-09 2002-05-08 Derivados de ciclohexan-1, 4 diamina substituìdos
NZ529147A NZ529147A (en) 2001-05-09 2002-05-08 Substituted cyclohexane-1,4-diamine derivatives
KR1020037014568A KR100895778B1 (ko) 2001-05-09 2002-05-08 치환된 사이클로헥산-1,4-디아민 유도체
SI200230571T SI1392641T1 (sl) 2001-05-09 2002-05-08 Substituirani cikloheksan-1,4-diaminski derivati
CA2446461A CA2446461C (en) 2001-05-09 2002-05-08 Substituted cyclohexane-1,4-diamine derivatives
HU0400888A HU228253B1 (en) 2001-05-09 2002-05-08 Substituted cyclohexane-1,4-diamine derivatives, process for their preparation and pharmaceutical compositions containing them
NO20034930A NO328600B1 (no) 2001-05-09 2003-11-05 Substituerte sykloheksan-1,4-diaminderivater, anvendelse derav, fremgangsmate for fremstilling derav og legemidler inneholdende slike derivater
IL158782A IL158782A (en) 2001-05-09 2003-11-06 Substituted cyclohexane - 1,4 - diamine derivatives, process for their preparation, medicaments comprising them and uses thereof for the preparation of medicaments
US10/704,329 US7276518B2 (en) 2001-05-09 2003-11-10 Substituted cyclohexane-1,4-diamine compounds
ZA2003/09522A ZA200309522B (en) 2001-05-09 2003-12-08 Substituted cyclohexane-1-4diamine derivatives
HK05102616.5A HK1070049A1 (en) 2001-05-09 2005-03-29 Substituted cyclohexane-1,4-diamine derivatives
CY20071100630T CY1106468T1 (el) 2001-05-09 2007-05-10 Υποκατεστημενα παραγωγα κυκλοεξανο-1,4-διαμινης

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US7232847B2 (en) 2002-11-12 2007-06-19 Gruenenthal Gmbh 4-hydroxymethyl-1-aryl-cyclohexylamine compounds
US7476763B2 (en) 2004-05-10 2009-01-13 Gruenenthal Gmbh Oxo-substituted cyclohexyl-1,4-diamine compounds
DE102004023507A1 (de) * 2004-05-10 2005-12-01 Grünenthal GmbH Substituierte Cyclohexylessigsäure-Derivate
WO2005110973A1 (de) 2004-05-10 2005-11-24 Grünenthal GmbH Saürederivate substituierter cyclohexyl-1,4-diamine
US8088763B2 (en) 2004-05-10 2012-01-03 Gruenenthal Gmbh Cyclohexyl-1, 4-diamine compounds
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US7786328B2 (en) 2004-05-10 2010-08-31 Gruenenthal Gmbh Cyclohexyl-1,4-diamine compounds
DE102004023501A1 (de) * 2004-05-10 2005-12-01 Grünenthal GmbH Oxosubstituierte Cyclohexyl-1,4-diamin-Derivate
DE102004023632A1 (de) * 2004-05-10 2005-12-08 Grünenthal GmbH Substituierte Cyclohexylcarbonsäure-Derivate
DE102004023508A1 (de) * 2004-05-10 2005-12-08 Grünenthal GmbH Säurederivate substituierter Cyclohexyl-1,4-diamine
WO2005110971A1 (de) 2004-05-10 2005-11-24 Grünenthal GmbH Heteroarylsubstituierte cyclohexyl-1,4-diamin-derivate
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US8017630B2 (en) 2004-05-10 2011-09-13 Gruenenthal Gmbh Cyclohexylacetic acid compounds
WO2005110975A1 (de) 2004-05-10 2005-11-24 Grünenthal GmbH Kettenverlängerte substituierte cyclohexyl-1,4-diamin-derivate
DE102004023506A1 (de) * 2004-05-10 2005-12-01 Grünenthal GmbH Kettenverlängerte substituierte Cyclohexyl-1,4-diamin-Derivate
WO2005110970A1 (de) 2004-05-10 2005-11-24 Grünenthal GmbH Oxosubstituierte cyclohexyl-1,4-diamin-derivate
US8058475B2 (en) 2005-12-22 2011-11-15 Gruenenthal Gmbh Substituted cyclohexylmethyl compounds
RU2459806C2 (ru) * 2006-07-18 2012-08-27 Грюненталь Гмбх Замещенные гетероарильные производные
US8399503B2 (en) 2006-07-18 2013-03-19 Gruenenthal Gmbh Spirocyclic azaindole derivatives
WO2008009415A2 (de) 2006-07-18 2008-01-24 Grünenthal GmbH 4-heteroaryl-substituierte 1-aminocyclohexan-1- und cyclohexen-1-derivate mit wirkung auf das opiod rezeptor system
US8062458B2 (en) 2006-07-28 2011-11-22 Tesa Se Method for stamping thermally activatable adhesive materials which are not tacky at room temperature
WO2009118168A1 (de) 2008-03-27 2009-10-01 Grünenthal GmbH Substituierte 4-aminocyclohexan-derivate
US9403767B2 (en) 2008-03-27 2016-08-02 Gruenenthal Gmbh Substituted 4-aminocyclohexane derivatives
US9580386B2 (en) 2008-03-27 2017-02-28 Grünenthal Substituted 4-aminocyclohexane derivatives
US7977370B2 (en) 2008-03-27 2011-07-12 Gruenenthal Gmbh (Hetero)aryl cyclohexane derivatives
US8293758B2 (en) 2008-03-27 2012-10-23 Grunenthal Gmbh Substituted spirocyclic cyclohexane derivatives
EP2518052A1 (de) 2008-03-27 2012-10-31 Grünenthal GmbH Substituierte 4-Aminocyclohexan-Derivate
US8357705B2 (en) 2008-03-27 2013-01-22 Gruenenthal Gmbh Substituted cyclohexyldiamines
US8288430B2 (en) 2008-03-27 2012-10-16 Grunenthal Gmbh Spiro(5.5)undecane derivatives
US8835689B2 (en) 2008-03-27 2014-09-16 Grünenthal GmbH Substituted 4-aminocyclohexane derivatives
RU2532545C2 (ru) * 2008-03-27 2014-11-10 Грюненталь Гмбх Замещенные производные 4-аминоциклогексана
WO2009118174A1 (de) 2008-03-27 2009-10-01 Grünenthal GmbH Substituierte cyclohexyldiamine
EP2502907A1 (de) * 2008-03-27 2012-09-26 Grünenthal GmbH Substitzierte 4-Aminocyclohexan-Derivate

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CA2446461C (en) 2011-04-26
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NO20034931D0 (no) 2003-11-05
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IL158782A (en) 2010-04-15
MXPA03010134A (es) 2004-03-10
DK1385825T3 (da) 2007-11-05
NO328600B1 (no) 2010-03-29
PE20021094A1 (es) 2003-01-25
HU228253B1 (en) 2013-02-28
DE10123163A1 (de) 2003-01-16
HUP0400989A3 (en) 2011-08-29
EP1392641A1 (de) 2004-03-03
ATE370120T1 (de) 2007-09-15
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JP2005515959A (ja) 2005-06-02
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CA2446463C (en) 2010-07-13
ECSP034830A (es) 2004-03-23
SI1385825T1 (sl) 2008-02-29
MXPA03010195A (es) 2004-03-10
SK287319B6 (sk) 2010-07-07
WO2002090330A1 (de) 2002-11-14
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EP1385493A1 (de) 2004-02-04
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PL366662A1 (en) 2005-02-07
US7276518B2 (en) 2007-10-02
CA2446461A1 (en) 2002-11-14
PL212887B1 (pl) 2012-12-31
RU2003134145A (ru) 2005-05-20
CA2446735A1 (en) 2002-11-14
RU2321579C2 (ru) 2008-04-10
ES2284876T3 (es) 2007-11-16
NO20034930D0 (no) 2003-11-05
PT1385825E (pt) 2007-09-04
ES2291486T3 (es) 2008-03-01
AU2007202033B2 (en) 2010-02-04
CN1307158C (zh) 2007-03-28
JP2004533439A (ja) 2004-11-04
US6998409B2 (en) 2006-02-14
PL368851A1 (en) 2005-04-04
RU2287523C2 (ru) 2006-11-20
BR0209580A (pt) 2004-06-22
HUP0400989A2 (hu) 2004-08-30
CY1106468T1 (el) 2012-01-25
NZ529334A (en) 2004-10-29
CN1533374A (zh) 2004-09-29
ECSP034831A (es) 2004-03-23
PL220595B1 (pl) 2015-11-30
US20040229872A1 (en) 2004-11-18
JP2004528374A (ja) 2004-09-16
ZA200309521B (en) 2004-09-28
DK1392641T3 (da) 2007-07-16
NO326784B1 (no) 2009-02-16
SK286617B6 (sk) 2009-02-05
EP1385825A1 (de) 2004-02-04
KR20040002943A (ko) 2004-01-07
SI1392641T1 (sl) 2007-10-31
RU2003134147A (ru) 2005-05-20
CO5540300A2 (es) 2005-07-29
IL158784A (en) 2009-09-01
KR20040017214A (ko) 2004-02-26
AU2002341195B2 (en) 2007-01-04
HUP0400888A3 (en) 2008-03-28
WO2002089783A1 (de) 2002-11-14
EP1392641B1 (de) 2007-04-11
PT1392641E (pt) 2007-05-31
EP1385825B1 (de) 2007-08-15
CZ20033005A3 (en) 2004-03-17
US20040147741A1 (en) 2004-07-29
HK1062911A1 (en) 2004-12-03
AU2002312883B2 (en) 2007-09-06
DE50210707D1 (de) 2007-09-27
AU2007202033B8 (en) 2010-03-04
NO20034931L (no) 2004-01-02
BR0209579A (pt) 2004-06-22
NZ529147A (en) 2006-10-27
CY1108067T1 (el) 2014-02-12
CZ20032995A3 (cs) 2004-02-18
CN1533374B (zh) 2013-08-21
HUP0400963A2 (hu) 2004-08-30
PL366631A1 (en) 2005-02-07
KR100895778B1 (ko) 2009-05-08
CA2446463A1 (en) 2002-11-14

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